1. Field of the Invention
The present invention relates to 1,2,3-triazole derivatives and, more particularly, to those capable of being used as cannabinoid CB1 receptor antagonists.
2. Description of Related Art
Obesity caused by an imbalance between food intake and energy expenditure, is a significant risk factor for cardiovascular disease and diabetes, and associated with significantly reduced life longevity. The World Health Organization (WHO) declared that obesity has become a global epidemic posing a serious threat to public health. The short-term diet or exercise is not effective as most obese patients readily regain their lost weight thereafter. Therefore, the medical treatment of obesity is an attractive approach.
In this respect, cannabinoid-1 receptor (CB1R) and its endogenous ligands (agonists), the endocannabinoids, have been found to be involved in the control of weight via a dual mechanism of food intake modification and the regulation of energy homeostasis. Indeed, the biological effects of the CB1 receptors, which are mainly located within the central nervous system, can be mediated through exposure to agonists or antagonists (inverse agonists). Blocking the effects of the endogenous cannabinoids has become a therapeutic avenue to treat obesity.
The other known cannabinoid receptor (CB2R), is predominantly found in the immune system and related to immune regulation. Therefore, good CB1/CB2 selectivity is a desired feature for the development of new anti-obesity drug. The most clinically advanced CB1 receptor antagonist, Rimonabant (SR141716A) launched by Sanofi-Aventis, binds to the human CB1 receptor with 5.6±0.5 nM (Ki) affinity (formula A). Since that development, many small molecule CB1 antagonists with diverse chemical structures have been prepared and reviewed. For example, Ibipinabant (SLV319), Otenabant (CP-945,598) and Taranabant (MK-0364) have been reported to be in various phases of clinical trials.
In addition to the pyrazole core of SR141716A, derivatives of other five-membered heterocycles, such as pyrrole, thiophene, thiazole, imidazole, oxazole, and 1,2,4-triazole are also known as the CB1 receptor antagonists. However, whether the derivatives of 1,2,3-triazole serve as CB1 receptor antagonists has not been explored yet.